title: Design of N-acylprolyltyrosine "tripeptoid" analogues of neurotensin as potential atypical antipsychotic agents.
abstract: A series of N-acylprolyltyrosine amides was designed as tripeptoid analogues of neurotensin. The substituted dipeptides were tested in vivo for antidopamine activity by their ability to inhibit the apomorphine-induced climbing in mice and the dopamine-induced extrapolatory behavior impairment in rats. The N-acylprolyltyrosine amides structure-activity relationships have indicated the size of the N-acyl group and the configuration of amino acids that are important for the activity. We found that the bioactivity has been increased dramatically when the n-hydrocarbon chain on the N-acyl group was increased from four to five carbon atoms. The activity seems to reside exclusively in the L-Tyr diastereomers. All of the compounds tested were inactive in the cataleptogenic action and did not exhibit the acute toxicity even at doses 500-1000 times higher than ED50 in climbing test. On this basis, the N-acylprolyltyrosine amides could potentially be a novel class of atypical antipsychotic agents.
authors.affiliation: Institute of Pharmacology, Russian Academy of Sciences, Moscow, Russia. uusolari@solaris.msk.ru
authors.forename: T A
authors.initials: TA
authors.lastname: Gudasheva
authors.forename: T A
authors.initials: TA
authors.lastname: Voronina
authors.forename: R U
authors.initials: RU
authors.lastname: Ostrovskaya
authors.forename: N I
authors.initials: NI
authors.lastname: Zaitseva
authors.forename: N A
authors.initials: NA
authors.lastname: Bondarenko
authors.forename: V K
authors.initials: VK
authors.lastname: Briling
authors.forename: L S
authors.initials: LS
authors.lastname: Asmakova
authors.forename: G G
authors.initials: GG
authors.lastname: Rozantsev
authors.forename: S B
authors.initials: SB
authors.lastname: Seredenin
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009496:Neurotensin / Q000031:analogs & derivatives*; D051381:Rats; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D009496:Neurotensin; D014443:Tyrosine